After advanced age, having a first-degree family history of late-onset Alzheimer's disease (AD), especially when a parent is affected, is the most significant risk factor for developing AD among cognitively normal (NL) subjects. We recently performed the first neuroimaging study to examine the effects of parental family history of AD on brain glucose metabolism (MRglc) in NL elderly. Using Positron Emission Tomography (FDG-PET), we discovered that NL subjects with a maternal family history of AD show reduced MRglc in the same brain regions as clinical AD patients, as compared to individuals with a paternal family history of AD and those without a family history of AD. With all that is known about the molecular processes involved in MRglc and about the pathophysiology of AD, the hypometabolism in NL individuals with a maternal family history of AD is likely due to, amongst other factors, a combination of defective mitochondrial function and increased oxidative damage, possibly related to mitochondrial DNA (mtDNA) deficits, that ultimately lead to MRglc alterations in brain tissue. The fact that mtDNA is exclusively maternally inherited in humans lends support to this hypothesis. The objective of this study is to examine the metabolic substrates through which a maternal family history of AD confers risk for developing dementia among NL elderly. We propose to examine the relationship between brain MRglc on FDG-PET and plasma markers of oxidative stress, such as increased production of reactive oxygen species (ROS) and reduced activitiy of mitochondrial electron transport chain (ETC) enzymes (i.e. Complex I, II, III and IV, and ATP-synthase) in 36 clinically and cognitively NL 65-80 year-old subjects, divided into 3 demographically matched groups of subjects with maternal (FHm) and paternal (FHp) family history of AD, and negative family history of AD (FH-). We will examine whether plasma ROS levels are increased and ETC enzymes activity is decreased in FHm as compared to FH- and FHp groups, and whether these effects are related with MRglc reductions in AD-vulnerable brain regions in FHm subjects. Detection of peripheral metabolic abnormalities in FHm subjects would indicate a systemic metabolic disorder that may change the oxidative microenvironment for neurons during the pathogenesis and progression of AD, rendering synapses more vulnerable to neurodegeneration. Our long-term objective is to improve our understanding of the pathophysiological and genetic mechanisms involved with AD, and provide evidence that may be useful for preclinical diagnostic purposes, to monitor disease progression, and to test the effectiveness of therapeutic interventions. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia. Normal individuals with a maternal family history of AD are at high risk for developing dementia and show reductions in brain glucose metabolism that may predispose these individuals to cognitive deterioration. We propose studies to clarify the origin of these metabolic reductions.